Publicação
Selection of single domain antibodies against the CD20 receptor: a new treatment with potencial anti-tumor properties for B-cell malignancies
| Resumo: | Lymphoma is the third most common neoplasia in the world. Within lymphomas, non-Hodgkin lymphoma (NHL) is the most common affecting mainly B cells. For more than three decades, chemotherapy and radiotherapy have been the only treatments available, but since the discovery of Rituximab, a new era of lymphoma therapy was inaugurated, once it was the first monoclonal antibody approved against the CD20 receptor. The CD20 receptor is an antigen expressed on the B-cells surface, and it is present nearly in all of its maturational development, being absent only in the stages of the pro-B lymphocyte and plasma cells. Furthermore, the CD20 receptor is also present on >90% of the B-cell NHL. These characteristics make this receptor an ideal target for immunotherapy. Besides the success of Rituximab, various mechanisms of resistance have been developed by the tumoral cells against this antibody, such as the decrease of the CD20 expression on B-cells, immunogenicity, structural changes affecting the binding region of the CD20 antibody or alterations in the cell membrane. New anti-CD20 antibodies have been developed to overcome the disadvantages of Rituximab, such as Ofatumumab and Obinutuzumab, presenting a different immunogenicity and binding to the different epitopes on the target with a different affinity. Apart from the progress in the lymphoma therapy, a significant population of patients still succumbs to this disease, as tumoral cells are always changing, making the search for better antibodies a never-ending process. Thus, the aim of this project consisted in the development and characterization of a new antibody against the CD20 receptor. To achieve this goal, the potential of rabbit derived single-domain antibodies (sdAbs) as therapeutic molecules were explored. For that, one rabbit was immunized with the CD20 receptor and an immune VH and VL sdAb library was generated. Then, a subtractive cell phage display screening was used for antibody selection. This approach allowed a specific selection of one sdAb in the VL format against the CD20 receptor in cells. In summary, the strategy explored in the present project resulted in an antibody that, according to its characteristics, could be a promising candidate in the treatment of NHL and other B-cell malignancies. |
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| Autores principais: | André, Ana Filipa Santos |
| Assunto: | CD20 Linfoma Imunoterapia Anticorpos de pequeno domínio Phage Display Teses de mestrado - 2016 |
| Ano: | 2016 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Lymphoma is the third most common neoplasia in the world. Within lymphomas, non-Hodgkin lymphoma (NHL) is the most common affecting mainly B cells. For more than three decades, chemotherapy and radiotherapy have been the only treatments available, but since the discovery of Rituximab, a new era of lymphoma therapy was inaugurated, once it was the first monoclonal antibody approved against the CD20 receptor. The CD20 receptor is an antigen expressed on the B-cells surface, and it is present nearly in all of its maturational development, being absent only in the stages of the pro-B lymphocyte and plasma cells. Furthermore, the CD20 receptor is also present on >90% of the B-cell NHL. These characteristics make this receptor an ideal target for immunotherapy. Besides the success of Rituximab, various mechanisms of resistance have been developed by the tumoral cells against this antibody, such as the decrease of the CD20 expression on B-cells, immunogenicity, structural changes affecting the binding region of the CD20 antibody or alterations in the cell membrane. New anti-CD20 antibodies have been developed to overcome the disadvantages of Rituximab, such as Ofatumumab and Obinutuzumab, presenting a different immunogenicity and binding to the different epitopes on the target with a different affinity. Apart from the progress in the lymphoma therapy, a significant population of patients still succumbs to this disease, as tumoral cells are always changing, making the search for better antibodies a never-ending process. Thus, the aim of this project consisted in the development and characterization of a new antibody against the CD20 receptor. To achieve this goal, the potential of rabbit derived single-domain antibodies (sdAbs) as therapeutic molecules were explored. For that, one rabbit was immunized with the CD20 receptor and an immune VH and VL sdAb library was generated. Then, a subtractive cell phage display screening was used for antibody selection. This approach allowed a specific selection of one sdAb in the VL format against the CD20 receptor in cells. In summary, the strategy explored in the present project resulted in an antibody that, according to its characteristics, could be a promising candidate in the treatment of NHL and other B-cell malignancies. |
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